Abstract: FR-PO351

Class IIa Histone Deacetylase Inhibition Suppresses Renal Fibroblast Activation and Lessens Fibrosis

Session Information

Category: Chronic Kidney Disease (Non-Dialysis)

  • 308 CKD: Mechanisms of Tubulointerstitial Fibrosis

Authors

  • Xiong, Chongxiang, Rhode Island Hospital, Providence, Rhode Island, United States
  • Zhuang, Shougang, Rhode Island Hospital, Alpert Medical School of Brown University, Providence, United States
Background

Histone deacetylases (HDACs) are a family of enzymes involved in regulation of cellular functions, including proliferation, migration and survival. Class I and III HDACs are associated with renal fibrosis. The role of class II HDAC in this process is poorly understood.

Methods

We examined the role of class IIa HDACs (HDAC- 4, -5, -7, -9) in renal fibroblast activation and fibrosis using MC1568, a highly selective class IIa HDAC inhibitor, and the siRNA specifically targeting individual class IIa HDACs.

Results

Exposing cultured renal interstitial fibroblasts to MC1568, or silencing class IIa HDAC-4 and-7, significantly reduced activation as indicated by decreased a-smooth muscle actin, collagen 1 and fibronectin expression. In a murine model of renal fibrosis induced by unilateral ureteral obstruction (UUO), HDAC-4 was highly expressed whereas expression levels of HDAC-5, -7, -9 were only slightly elevated. MC1568 suppressed deposition of extracellular matrix proteins and renal fibroblast activation. This coincided with reduced numbers of renal epithelial cells arrested at G2/M cell cycle phase and restored expression of Klotho and BMP7 after UUO injury. MC1568 also abrogated UUO-induced phosphorylation of receptor tyrosine kinases (epidermal growth factor and platelet growth factor receptors) and several signaling molecules associated with renal fibrosis, including Smad-3, STAT3, and NF-κB and ERK1/2. Moreover, class IIa inhibition suppressed renal expression of HIF-1α, Notch-1 and -3 and preserved expression of PPAR-alpha and PPAR-gama following UUO.

Conclusion

Class IIa HDACs inhibition may attenuate renal fibrosis by inhibiting profibrotic signaling pathways and preserving expression of renoprotective factors.

Funding

  • NIDDK Support